The present invention concerns the analgesic activity of the l-(levorotary) isomer and the racemate of the alkaloid glaucine, which occurs naturally in the d-(dextrorotary) form. Merck Index, Ninth Ed., Merck & Co., Rahway, N.J. (1976) Monograph 4267.
D-glaucine hydrobromide and d-glaucine hydrobromide are known to have antitussive activity. Donev, Farmatsia (Pharmacy) (Sofia) 1962, No 4, p. 17, and Aleshinskaya, Khim. Farm. Zh. 10, (1), 144-147 (1976) Chem. Abstr. 84:159725 w. In addition, Aleshinskaya, supra, stated that glaucine derived from the yellow horned poppy (d-glaucine), prolongs hexenal and chloral hydrate sleep time in mice, and has analgesic activity at doses of 50-100 mg/kg, as well as adrenolytic activity.
Pharmacological stereospecificity is well known, and there are numerous instances of dramatic differences exhibited by biologically active enantiomers in their interactions with living organisms. Thus, the naturally-occurring levorotary alkaloid, morphine, is a powerful analgesic, while the synthetic dextrorotary enantiomorph is not. One enantiomer, D-(-)-threo-chloramphenicol (the natural product) is a potent antibiotic, while others, such as L-(+)-threo-chloramphenicol, are not. L-(-)-ascorbic acid has antiscorbutic properties, but (+)-ascorbic acid does not; (+)-muscarine has 700 times the muscarinic activity of (-) muscarine; D-(-)-epinephrine is a much more potent vasoconstrictor than D-(+)-epinephrine; and natural (+)-cortisone and (+)-aldosterone are active, racemates have half this activity and the (-) isomers, levorotary isomers, are inactive. Mislow, Introduction to Stereochemistry, W. A. Benjamine, Inc. New York & Amsterdam (1966), p. 137; A. Korolkovas, Essentials of Molecular Pharmacology, Witey Interscience, New York (1970) 97-101, 188-189; Casy, Analgesic Receptors, in A Guide to Molecular Pharmacology-Toxicology, Ed. Featherstone, Marcel Dekker, Inc. New York (1973) Part I, pp 240-246.
Stereospecificity also occurs in synthetic compounds. For example, levo-3-hydroxy-N-methyl isomorphinan is a potent analgesic; the dextro isomer is not (Casy, supra. p. 240) and dextropropoxyphene is a potent analgesic, while levopropoxyphene is not. Merck Index, supra, Monographs 7627 and 5315.
D-glaucine can be isolated from the yellow poppy. The racemate, d,l-glaucine can be synthesized from papaverine, following the procedure of Frank and Tietze, Angewandte Chemie (1967) pp 815-6. A variety of other preparative procedures are also known. Cham and Maitland, J. Org. Chem. J. Chem. Soc. (C) 1966, 753; and Cava, et al. J. Org. Chem. 35, 175 (1970). Separation of the isomers has been carried out by conventional procedures, such as using d,l-tartaric acid to form the d- and l-tartrate salts and separating the salts by fractional cyrstallization.
Glaucine has the structure ##STR1## and is thus structurally related to other plant alkaloids such as codeine.
Codeine, and related compounds such as hydrocodone, are well known as narcotic analgesic agents. Merck Index, Ninth Ed., Merck & Co., Rahway, N.J. (1976) monographs Nos. 2420-24 and 4672. Although these compounds are also well known to have a high potential for habituation or addication, they remain among the most potent and widely used agents.